A trans-omics assessment of gene-gene interaction in early-stage NSCLC.
A trans-omics assessment of gene-gene interaction in early-stage NSCLC.
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DOI：
10.1002/1878-0261.13345
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发表时间：
2023-01
影响因子：
6.6
通讯作者：
Chen, Feng
中科院分区：
文献类型：
--
作者：
Chen, Jiajin;Song, Yunjie;Li, Yi;Wei, Yongyue;Shen, Sipeng;Zhao, Yang;You, Dongfang;Su, Li;Bjaanaes, Maria Moksnes;Karlsson, Anna;Planck, Maria;Staaf, Johan;Helland, Aslaug;Esteller, Manel;Shen, Hongbing;Christiani, David C. C.;Zhang, Ruyang;Chen, Feng
与非小细胞肺癌（NSCLC）生存相关的全表观基因组基因 - 基因（G×G）相互作用可能为分子机制和治疗靶点提供见解。因此，我们提出了一种三步分析策略，以识别与NSCLC生存相关的显著且稳健的G×G相互作用。在第一步中，在490亿对DNA甲基化探针中，我们在表观基因组分析的发现阶段确定了175775个G×G相互作用，其Bonferroni校正P值≤0.05；其中，15534个在验证阶段P值≤0.05得到确认。在第二步中，我们通过两阶段（发现和验证）转录组分析在基因表达水平上对这些G×G相互作用进一步进行功能验证，并确认了25个显著的G×G相互作用，它们富集在6p21.33和6p22.1区域。在第三步中，我们使用跨组学分析确定了两个G×G相互作用，它们在表观遗传和转录水平上都具有显著（P≤0.05）的表观遗传顺式转录调控以及稳健的G×G相互作用。这些相互作用是cg14391855×cg23937960（相互作用系数β = 0.018，P = 1.87×10⁻¹²），其对应于RELA×HLA - G（相互作用系数β = 0.218，P = 8.82×10⁻¹¹）以及cg08872738×cg27077312（相互作用系数β = -0.010，P = 1.16×10⁻¹¹），其对应于TUBA1B×TOMM40（相互作用系数β = -0.250，P = 3.83×10⁻¹⁰）。一项跨组学中介分析显示，20.3%的表观遗传对NSCLC生存的影响通过转录表达显著（P = 0.034）介导。这些具有统计学意义的跨组学G×G相互作用也能够区分具有高死亡风险的患者。总之，我们在表观遗传和转录水平上确定了两个G×G相互作用，我们的研究结果可能为NSCLC的精准治疗提供潜在线索。
一项三步跨组学研究确定了两个基因 - 基因相互作用，cg14391855×cg23937960（对应于RELA×HLA - G）以及cg08872738×cg27077312（对应于TUBA1B×TOMM40），它们在表观遗传和转录水平上都与NSCLC生存显著且稳健相关。我们的研究结果通过为早期NSCLC患者提供治疗靶点，对精准治疗具有启示意义。
Epigenome‐wide gene–gene (G × G) interactions associated with non‐small‐cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three‐step analytic strategy to identify significant and robust G × G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175 775 G × G interactions with P Bonferroni ≤ 0.05 in the discovery phase of epigenomic analysis; among them, 15 534 were confirmed with P ≤ 0.05 in the validation phase. In the second step, we further performed a functional validation for these G × G interactions at the gene expression level by way of a two‐phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G × G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G × G interactions using the trans‐omics analysis, which had significant (P ≤ 0.05) epigenetic cis‐regulation of transcription and robust G × G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 × cg23937960 (β interaction = 0.018, P = 1.87 × 10−12), which mapped to RELA × HLA‐G (β interaction = 0.218, P = 8.82 × 10−11) and cg08872738 × cg27077312 (β interaction = −0.010, P = 1.16 × 10−11), which mapped to TUBA1B × TOMM40 (β interaction =−0.250, P = 3.83 × 10−10). A trans‐omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P = 0.034) mediated through transcriptional expression. These statistically significant trans‐omics G × G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G × G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC. A three‐step, trans‐omics study identified two gene–gene interactions, cg14391855 × cg23937960 (mapped to RELA × HLA‐G) as well as cg08872738 × cg27077312 (mapped to TUBA1B × TOMM40), which were significantly and robustly associated with NSCLC survival at both the epigenetic and transcriptional levels. Our findings have implications of precision treatment by providing therapeutic targets for early‐stage NSCLC patients.
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影响因子：
3.7
作者：
Marabita F;Almgren M;Lindholm ME;Ruhrmann S;Fagerström-Billai F;Jagodic M;Sundberg CJ;Ekström TJ;Teschendorff AE;Tegnér J;Gomez-Cabrero D
通讯作者：
Gomez-Cabrero D
DOI：
10.1038/nrg2579
发表时间：
2009-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Cordell HJ
通讯作者：
Cordell HJ
影响因子：
6.6
作者：
Bjaanæs MM;Fleischer T;Halvorsen AR;Daunay A;Busato F;Solberg S;Jørgensen L;Kure E;Edvardsen H;Børresen-Dale AL;Brustugun OT;Tost J;Kristensen V;Helland Å
通讯作者：
Helland Å
全表观基因组基因年龄相互作用分析揭示 PRODH DNA 甲基化对年轻和老年早期 NSCLC 患者生存的逆转影响
影响因子：
5.2
作者：
Chen, Chao;Wei, Yongyue;Christiani, David C.
通讯作者：
Christiani, David C.
影响因子：
28.2
作者：
Gu SS;Zhang W;Wang X;Jiang P;Traugh N;Li Z;Meyer C;Stewig B;Xie Y;Bu X;Manos MP;Font-Tello A;Gjini E;Lako A;Lim K;Conway J;Tewari AK;Zeng Z;Sahu AD;Tokheim C;Weirather JL;Fu J;Zhang Y;Kroger B;Liang JH;Cejas P;Freeman GJ;Rodig S;Long HW;Gewurz BE;Hodi FS;Brown M;Liu XS
通讯作者：
Liu XS